A landmark study has revealed that cholesterol in the brain may play a fundamental role in catalyzing the formation of amyloid beta clusters, thought to be a central mechanism leading to the devastating degenerative symptoms of Alzheimer's disease.
An international team of researchers, led by the University of Cambridge, set out to uncover what causes amyloid beta proteins to cluster into the plaques that slowly accumulate and cause the primary degenerative symptoms of Alzheimer's disease.
"The levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory – so what happens in the brain to make it aggregate?" asks Michele Vendruscolo, lead on the new research.
Although notorious as a molecule linked with cardiovascular disease, cholesterol is a terribly important compound, present in the membranes that surround all our cells. Cholesterol in the brain is especially fundamental to the organ working properly. Up to 25 percent of all cholesterol in the body is found in the brain, and studies have shown without that cholesterol our brains simply do not function.
Because the blood-brain barrier generally blocks cholesterol in the blood from entering the brain, the organ has developed its own processes to generate the molecule independent from the rest of the body. So high levels of blood cholesterol, which could lead to cardiovascular problems, do not necessarily correlate with high levels of brain cholesterol.
The new research, examining what causes amyloid beta proteins to aggregate, found that cholesterol in lipid cell membranes in the brain tends to trigger the accumulation of amyloid beta molecules. The study dramatically reports that in vitro modeling shows aggregation of amyloid beta is sped up by a factor of 20 in the presence of cholesterol.
Of course, due to the complex interaction between brain function and cholesterol, the takeaway here is not that simply reducing brain cholesterol will protect one from Alzheimer's. After all, the brain needs cholesterol to effectively function.
"The question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol's role in Alzheimer's disease through the regulation of its interaction with amyloid-beta," says Vendruscolo. "We're not saying that cholesterol is the only trigger for the aggregation process, but it's certainly one of them."
Over recent years, there has been divisive and inconclusive research regarding the effect of cholesterol-lowering statins on cognitive function. While some research, with very small cohorts, has indeed suggested statin-use results in cognitive decline, other studies have found the exact opposite effect, with subjects displaying a lower risk of dementia.
This new research seems to offer an interesting potential explanation for such discrepancies, highlighting the different biochemical pathways that can result in dementia. For some, cholesterol-reducing medications may result in protective effects on cognition by reducing the aggregation of amyloid beta clusters in the brain that lead to Alzheimer's, while for others the drugs could possibly be problematic.
For those taking, and needing, cholesterol-reducing medications, it is not at all suggested they stop taking those drugs, but further research into this compelling new area could unlock novel ways to address cognitive decline by hijacking these brain mechanisms.
The study was published in the journal Nature Chemistry.
Source: University of Cambridge
